There is a knowledge gap regarding the treatment patterns of patients with major depressive disorder (MDD) who experience suicidal ideation or a suicide attempt (SI/SA).
Patients with SI/SA were ...identified from a large US-based claims database covering 84 million lives, during 1/1/2014-3/31/2020. Patients with MDD were indexed at their first diagnosis for SI/SA and followed up to 365 days. Treatment patterns were captured at the class level and included procedures of electroconvulsive therapy and transcranial magnetic stimulation, and pharmacotherapy including selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, other antidepressants, anxiolytics, hypnotics/sedatives, antipsychotics, psychostimulants, and lithium.
There were 42,204 MDD + SI/SA patients identified. In the year prior to the index event > 40% of individuals received an SSRI and more than one-third received an anxiolytic. Within 1 year following, 84.4% received ≥1 of the treatments of interest. Of those, 70.2% went on to a subsequent class-based regimen, 46.3% received a third, and 28.1% received ≥4. More than three-quarters of patients received multiple treatment classes simultaneously. SSRIs were the most common treatments during follow-up (61.9%), followed by other antidepressants (51.3%), anxiolytics (50.8%) and anticonvulsants (43.6%).
There was a large amount of variability and polypharmacy in the treatments received by MDD patients with SI/SA, and is much more complex than what has been previously observed in the general MDD population. Within one-year, many patients received four or more unique class-based regimens and most patients received treatments from multiple classes simultaneously, indicating the high unmet medical need and therapy refractoriness of this patient population.
Background
Major depressive disorders (MDDs) including treatment-resistant depression (TRD) are common disabling conditions, but data on their epidemiology in Japan are limited. This study ...investigated the incidence, epidemiology, and direct medical costs of TRD and pharmaceutically-treated depression (PTD) in Japan to increase our health economic understanding of this phenotype of MDD.
Methods
A retrospective cohort study from a private health insurance claims database estimated the 1-year incidence of PTD and TRD and described the health services used and direct medical costs associated with these conditions.
Results
In the year from 1 April 2012 through 31 March 2013, we identified 1143 incident PTD cases among 98,552 eligible subjects, i.e. 11.59 cases/1000 patient-years. Of the PTD patients, 51.4% were women. Within the 1-year observation interval 137 patients failed more than two antidepressive treatment approaches and thus developed TRD. Though co-morbid conditions and age were similar among PTD and TRD patients, medical costs per patient (patient-year) during their treatment intervals were 1.01 million JPY (0. 540 million JPY) in the TRD population and 0.643 JPY million JPY (0.645 million JPY) in the PTD population who did not convert into TRD.
Conclusions
This study describes the PTD and TRD patient populations in a large claims database in Japan and highlights an unmet medical need for the treatment of TRD to provide better preventative measures and interventions for the treatment of depression.
We applied serial analysis of gene expression (SAGE) to study differentially expressed genes in mouse brain 14 hr after the induction of focal cerebral ischemia. Analysis of >60,000 transcripts ...revealed 83 upregulated and 94 downregulated transcripts (more than or equal to eightfold). Reproducibility was demonstrated by performing SAGE in duplicate on the same starting material. Metallothionein-II (MT-II) was the most significantly upregulated transcript in the ischemic hemisphere. MT-I and MT-II are assumed to be induced by metals, glucocorticoids, and inflammatory signals in a coordinated manner, yet their function remains elusive. Upregulation of both MT-I and MT-II was confirmed by Northern blotting. MT-I and MT-II mRNA expression increased as early as 2 hr after 2 hr of transient ischemia, with a maximum after 16 hr. Western blotting and immunohistochemistry revealed MT-I/-II upregulation in the ischemic hemisphere, whereas double labeling demonstrated the colocalization of MT with markers for astrocytes as well as for monocytes/macrophages. MT-I- and MT-II-deficient mice developed approximately threefold larger infarcts than wild-type mice and a significantly worse neurological outcome. For the first time we make available a comprehensive data set on brain ischemic gene expression and underscore the important protective role of metallothioneins in ischemic damage of the brain. Our results demonstrate the usefulness of SAGE to screen functionally relevant genes and the power of knock-out models in linking function to expression data generated by high throughput techniques.
In this article we describe the DTA “Base Format” (DTABf), a strict subset of the TEI P5 tag set. The purpose of the DTABf is to provide a balance between expressiveness and precision as well as an ...interoperable annotation scheme for a large variety of text types of historical corpora of printed text from multiple sources. The DTABf has been developed on the basis of a large amount of historical text data in the core corpus of the project Deutsches Textarchiv (DTA) and text collections from 15 cooperating projects with a current total of 210 million tokens. The DTABf is a “living” TEI format which is continuously adjusted when new text candidates for the DTA containing new structural phenomena are encountered. We also focus on other aspects of the DTABf including consistency, interoperability with other TEI dialects, HTML and other presentations of the TEI texts, and conversion into other formats, as well as linguistic analysis. We include some examples of best practices to illustrate how external corpora can be losslessly converted into the DTABf, thus enabling third parties to use the DTABf in their specific projects. The DTABf is comprehensively documented, and several software tools are available for working with it, making it a widely used format for the encoding of historical printed German text.
Abstract Background The purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant ...depression (TRD). Methods This multicenter, randomized, placebo-controlled trial was conducted in 30 patients with TRD. Patients were randomly assigned 1:1:1 to receive an IV infusion of .20 mg/kg or .40 mg/kg esketamine or placebo over 40 minutes on day 1. The primary end point was change in Montgomery–Åsberg Depression Rating Scale total score from day 1 (baseline) to day 2. Nonresponders who received placebo on day 1 were randomly assigned again 1:1 to IV esketamine .20 mg/kg or .40 mg/kg on day 4. Secondary efficacy and safety measures were also evaluated. Results Of the enrolled patients, 97% (29 of 30) completed the study. The least squares mean changes (SE) from baseline to day 2 in Montgomery–Åsberg Depression Rating Scale total score for the esketamine .20 mg/kg and .40 mg/kg dose groups were −16.8 (3.00) and −16.9 (2.61), respectively, and showed significant improvement (one-sided p = .001 for both groups) compared with placebo (−3.8 2.97). Esketamine showed a rapid (within 2 hours) and robust antidepressant effect. Treatment-emergent adverse events were dose dependent. The most common treatment-emergent adverse events were headache, nausea, and dissociation; the last-mentioned was transient and did not persist beyond 4 hours from the start of the esketamine infusion. Conclusions A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-min IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy.
Stroke and head trauma are worldwide public health problems and leading causes of death and disability in humans, yet, no adequate neuroprotective treatment is available for therapy. Glutamate ...antagonists are considered major drug candidates for neuroprotection in stroke and trauma. However, N-methyl-D-asparate antagonists failed clinical trials because of unacceptable side effects and short therapeutic time window. α -Amino-3-hydroxyl-5-methyl-4-isoxazolepropionate (AMPA) antagonists derived from the quinoxalinedione scaffold cannot be used in humans because of their insolubility and resulting renal toxicity. Therefore, achieving water solubility of quinoxalinediones without loss of selectivity and potency profiles becomes a major challenge for medicinal chemistry. One of the major tenets in the chemistry of glutamate antagonists is that the incorporation of phosphonate into the glutamate framework results in preferential N-methyl-D-aspartate antagonism. Therefore, synthesis of phosphonate derivatives of quinoxalinediones was not pursued because of a predicted loss of their selectivity toward AMPA. Here, we report that introduction of a methylphosphonate group into the quinoxalinedione skeleton leaves potency as AMPA antagonists and selectivity for the AMPA receptor unchanged and dramatically improves solubility. One such novel phosphonate quinoxalinedione derivative and competitive AMPA antagonist ZK200775 exhibited a surprisingly long therapeutic time window of >4 h after permanent occlusion of the middle cerebral artery in rats and was devoid of renal toxicity. Furthermore, delayed treatment with ZK200775 commencing 2 h after onset of reperfusion in transient middle cerebral artery occlusion resulted in a dramatic reduction of the infarct size. ZK200775 alleviated also both cortical and hippocampal damage induced by head trauma in the rat. These observations suggest that phosphonate quinoxalinedione-based AMPA antagonists may offer new prospects for treatment of stroke and trauma in humans.
•Clinicians may often be unaware of career opportunities outside of patient care.•Structures of pharmaceutical companies may vary based on therapeutic focus & size.•Career paths are diverse and ...adaptable to a candidate’s strengths and interests.•Physicians often occupy positions in R&D, safety, regulatory or medical affairs.
Although physicians occupy a significant number of key positions in the pharmaceutical industry, practicing clinicians are often unaware of the variety of career paths within this industry, or of the structure of a pharmaceutical company. Here, we address questions that practicing clinicians frequently ask their colleagues in the pharmaceutical industry. In addition to providing an overview of the common roles occupied by physicians in pharma, we also describe the various motivations for transitioning into the industry and discuss different scenarios regarding the timing of the career change. Furthermore, we outline the characteristics and skills that enable physicians to have a successful career in pharma.
Among mass digitization methods, double-keying is considered to be the one with the lowest error rate. This method requires two independent transcriptions of a text by two different operators. It is ...particularly well suited to historical texts, which often exhibit deficiencies like poor master copies or other difficulties such as spelling variation or complex text structures. Providers of data entry services using the double-keying method generally advertise very high accuracy rates (around 99.95% to 99.98%). These advertised percentages are generally estimated on the basis of small samples, and little if anything is said about either the actual amount of text or the text genres which have been proofread, about error types, proofreaders, etc. In order to obtain significant data on this problem it is necessary to analyze a large amount of text representing a balanced sample of different text types, to distinguish the structural XML/TEI level from the typographical level, and to differentiate between various types of errors which may originate from different sources and may not be equally severe. This paper presents an extensive and complex approach to the analysis and correction of double-keying errors which has been applied by the DFG-funded project "Deutsches Textarchiv" (German Text Archive, hereafter DTA) in order to evaluate and preferably to increase the transcription and annotation accuracy of double-keyed DTA texts. Statistical analyses of the results gained from proofreading a large quantity of text are presented, which verify the common accuracy rates for the double-keying method.
To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of BPL-003, a novel intranasal benzoate salt formulation of 5-methoxy-
-dimethyltryptamine (5-MeO-DMT), in ...healthy participants.
In all, 44 psychedelic-naïve participants enrolled in the double-blind, placebo-controlled single ascending dose study (1-12 mg BPL-003). Concentrations of 5-MeO-DMT and its pharmacologically active metabolite, bufotenine, were determined in plasma and urine. PD endpoints included subjective drug intensity (SDI) rating, the Mystical Experience Questionnaire (MEQ-30) and the Ego Dissolution Inventory (EDI).
BPL-003 was well tolerated at doses up to 12 mg. There were no serious adverse events (AEs), and most AEs were mild; the most common being nasal discomfort, nausea, headache and vomiting. 5-MeO-DMT was rapidly absorbed and eliminated; the median time to peak plasma concentration was approximately 8-10 min and the mean terminal elimination half-life was <27 min. 5-MeO-DMT systemic exposure increased approximately dose-proportionally, while plasma bufotenine concentrations and urinary excretion of 5-MeO-DMT and bufotenine were negligible. The intensity of the SDI ratings was associated with plasma 5-MeO-DMT concentrations. MEQ-30 and EDI scores generally increased with the BPL-003 dose; 60% of participants had a 'complete mystical experience' at 10 and 12 mg doses. Profound and highly emotional consciousness-altering effects were observed with BPL-003, with a rapid onset and short-lasting duration.
The novel intranasal formulation of BPL-003 was well tolerated with dose-proportional increases in PK and PD effects. The short duration of action and induction of mystical experiences suggest clinical potential, warranting further trials.
NCT05347849.
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